Induced phase transition method for the production of microparticles containing hydrophobic active agents

Abstract

Microparticles and a method for their production is described. The process of the present invention provides a simple, quick, and efficient one-pot process for the production of microparticles containing a non-water soluble active agent. The microparticles are preferably used for pharmaceutical applications and comprise at least 80 wt % microspheres.

Description

CROSS REFERENCES TO RELATED APPLICATION[0001]This application claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 60 / 257,527, filed Dec. 31, 2000, and U.S. Provisional Patent Application Ser. No. 60 / 300,021, filed Jun. 21, 2001, the disclosures of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]This invention is directed to a process for the production of microparticles containing a non-water soluble biologically active, as well as the microparticles produced by this process. According to the invention, a simplified one-pot process for producing such microparticles is provided.BACKGROUND OF THE INVENTION[0003]Many biologically active drugs possess strong lipophilic properties, which result in negligible solubility in water. The development of an appropriate formulation of these active substances therefore is a challenging problem.[0004]One alternative to currently available formulations of these pharmacologically active substances is...

AI Technical Summary

Benefits of technology

[0046]The present invention provides a novel, simple and mild process for the encapsulation of non-water soluble active agents in biodegradable polymers which avoids or reduces the disadvantages seen in the prior art. The process produces non-agglomerating, microparticles in the size range from 20 nm to 1,000 μm at encapsulation efficiencies of greater than 85%, preferably greater than 90% using toxico

Problems solved by technology

Many biologically active drugs possess strong lipophilic properties, which result in negligible solubility in water.

The development of an appropriate formulation of these active substances therefore is a challenging problem.

However, most all prior art processes use halogenated hydrocarbons as solvent (dichloromethane or chloroform), which have enormous toxicological potential (Henschler.

However, the solvent evaporation technique is often not preferred because active ingredient is often lost during the solvent extraction process.

However, the levels of incorporation of the hydrophilic active ingredient into the microspheres relative to the amounts employed in the process are fairly low and, moreover, this system involves a limitation with respect to the types of polymers which may be used given that it requires the polymer to be soluble in acetone, which is the case with lactic acid polymers, but which is not the case for lactic acid and glycolic acid copolymers.

This technique by emulsion/evaporation is therefore traditionally recognized as unsuitable for water-soluble peptides and for all water-soluble substances.

As already mentioned above, the employed halogenated solvents are also toxicologically objectionable.

This method also requires large amounts of surfactants.

Again, this process suffers primarily from loss of active ingredient due to denaturation.

The main disadvantage of this method is the use of large amounts of solvents with, in addition to cost constraints, problems of toxicity linked to the solvents, such as heptane, used.

This is because the techniques by coacervation using heptane do not enable its complete removal.

Independently of the above, it has also been observed that aggregates of microspheres causing a high loss of yield in the production of these microspheres by this method and sometimes requiring the total rejection of some batches which have thus become unusable, were often produced.

The tendency of the microspheres to aggregate causes additional difficulties at the time of suspending the microspheres for injection, in the

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